Ramelteon, sold under the brand name Rozerem among others, is a

melatonin agonist Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The dis ...

medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth. Side effects of ramelteon include somnolence, dizziness,

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, nausea, exacerbated insomnia, and changes in hormone levels. Ramelteon is an analogue of

melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrates ...

and is a selective

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

MT₁ and MT₂ receptors. The half-life and

duration Duration may refer to: * The amount of time elapsed between two events * Duration (music) – an amount of time or a particular time interval, often cited as one of the fundamental aspects of music * Duration (philosophy) – a theory of time and ...

of ramelteon are much longer than those of melatonin. Ramelteon is not a

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

or Z-drug and does not interact with

GABA receptor The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...

s, instead having a distinct mechanism of action. Ramelteon was first described in 2002 and was approved for medical use in 2005. Unlike certain other sleep medications, ramelteon is not a controlled substance and has no known

potential for misuse Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...

Medical uses

Insomnia

Ramelteon is approved for the treatment of insomnia characterized by difficulty with sleep onset in adults. In regulatory clinical trials, it was found to significantly reduce latency to persistent sleep (LPS). A 2009 pooled analysis of four clinical trials found that ramelteon at a dose of 8 mg reduced sleep onset by 13 minutes (30% decrease) relative to placebo on the first and second nights of use. Subsequent meta-analyses of longer-duration use have found that ramelteon decreases

subjective sleep latency In sleep science, sleep onset latency (SOL) is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages. Sleep latency studies Pioneering Stanford Universi ...

by about 4 to 7 minutes. Meta-analyses are mixed on whether ramelteon increases total sleep time. Ramelteon also improves sleep quality ( –0.074, 95% –0.13 to –0.02) and sleep efficiency. The clinical improvement in insomnia with ramelteon is small and of questionable benefit. Ramelteon is approved in the United States but was not approved in the European Union owing to concerns that it lacked effectiveness. The Committee for Medicinal Products for Human Use (CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) noted that ramelteon had only been found to improve sleep onset and not other sleep outcomes, only one of three clinical trials actually found that it improved sleep onset, and that the improvement in sleep onset was too small to be clinically meaningful. The CHMP also noted that the long-term effectiveness of ramelteon had not been demonstrated. The

American Academy of Sleep Medicine The American Academy of Sleep Medicine (AASM) is a United States professional society for the medical subspecialty of sleep medicine which includes disorders of circadian rhythms. It was established in 1975. The organization's functions include t ...

's 2017 clinical practice guidelines recommended the use of ramelteon in the treatment of sleep-onset insomnia. It rated the recommendation as weak and the

quality of evidence Evidence-based medicine (EBM) is "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients". The aim of EBM is to integrate the experience of the clinician, the values of t ...

as very low but concluded that the potential benefits outweighed the potential harms. The guidelines found that ramelteon reduces sleep latency by 9minutes (95% 6–12minutes) but does not improve sleep quality. In contrast to ramelteon, the guidelines did not recommend the use of

Circadian rhythm sleep disorders

Melatonin receptor agonists like

and

tasimelteon Tasimelteon, sold under the brand name Hetlioz, is a medication approved by the U.S. Food and Drug Administration (FDA) in January 2014, for the treatment of non-24-hour sleep–wake disorder (also called non-24, N24 and N24HSWD). In June 2014, th ...

are considered to be effective in regulating sleep–wake cycles and in the treatment of

circadian rhythm sleep disorder Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be ...

s like delayed sleep phase disorder. Ramelteon has been assessed in only a few studies in the treatment of circadian rhythm sleep disorders, including

jet lag disorder Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. from ...

shift work disorder Shift work sleep disorder (SWSD) is a circadian rhythm sleep disorder characterized by insomnia, excessive sleepiness, or both affecting people whose work hours overlap with the typical sleep period. Insomnia can be the difficulty to fall asleep o ...

, and non-24-hour sleep–wake disorder. These studies have been of varying quality and their findings in terms of effectiveness have been mixed. Ramelteon is approved only for treatment of insomnia and is not approved for treatment of circadian rhythm sleep disorders. It was previously under development for treatment of circadian rhythm sleep disorders, but development for these indications was discontinued.

Other uses

Delirium

A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo." A 2022 systematic review and meta-analysis found that the combination of ramelteon and the orexin receptor antagonist

suvorexant Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or mainte ...

may reduce the incidence of

delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in ...

in adults

hospitalized A hospital is a health care institution providing patient treatment with specialized health science and auxiliary healthcare staff and medical equipment. The best-known type of hospital is the general hospital, which typically has an emergency ...

patients whereas suvorexant alone was ineffective.

Bipolar disorder

Ramelteon has received attention in psychiatry as a possible add-on treatment for

mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...

in bipolar disorder. However, to date, the scarce available evidence fails to support the clinical utility of ramelteon and other melatonin receptor agonists such as

for mania.

Available forms

Ramelteon is available in the form of 8 mg oral film-coated

tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the s ...

Contraindications

Ramelteon is not recommended for use in people with severe sleep apnea.

Adverse effects

Side effects of ramelteon include somnolence (3% vs. 2% for placebo),

(3% vs. 2% for placebo), dizziness (4% vs. 3% for placebo), nausea (3% vs. 2% for placebo), and exacerbated insomnia (3% vs. 2% for placebo). Overall, side effects occurred in 6% with ramelteon and 2% with placebo in clinical trials. Side effects leading to discontinuation occurred in 1% or fewer people. Rarely, anaphylactic reactions,

abnormal thinking A thought disorder (TD) is any disturbance in cognition that adversely affects language and thought content, and thereby communication. A variety of thought disorders were said to be characteristic of people with schizophrenia. A content-thought ...

, and worsening of depression or

suicidal thinking Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...

in patients with pre-existing depression may occur with ramelteon. Ramelteon has been found to slightly increase prolactin levels in women (+34% vs. –4% with placebo) but not in men and to decrease free testosterone levels (by 3–6% in younger men and by 13–18% in older men). Ramelteon has not been shown to produce dependence and has shown no potential for abuse. The

withdrawal Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * ''Coitus interruptus'' (the withdrawal method) * Drug withdrawal * Social withdrawal * Taking of money from a ban ...

and

rebound insomnia The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...

that is typical with GABA_A receptor positive modulators like

s and Z-drugs is not present in ramelteon. Increased incidence of liver and testicular tumors have been observed with ramelteon in rodents but only at doses equivalent to at least 20 times greater than the recommended dose in humans.

Overdose

Ramelteon has been assessed at doses of up to 64 mg in clinical studies.

Interactions

Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam,

digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...

and warfarin. There were no clinically meaningful effects when ramelteon was coadministered with any of these drugs. A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were coadministered. When coadministered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the C_max increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be coadministered. has significant drug–drug interaction with the following drugs: . Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

inhibitors such as

ketoconazole Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...

, and strong CYP2C9 inhibitors such as fluconazole. Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.

Pharmacology

Pharmacodynamics

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT₁ and MT₂ receptors and

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

over the non-human MT₃ receptor. Ramelteon demonstrates full agonist activity ''in vitro'' in cells expressing human MT₁ or MT₂ receptors, and high selectivity for human MT₁ and MT₂ receptors compared to the non-human MT₃ receptor. The

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Partn ...

of ramelteon for the MT₁ and MT₂ receptors is 3 to 16 times higher than that of melatonin. Ramelteon has 8-fold higher affinity for the MT₁ receptor over the MT₂ receptor. The binding profile of ramelteon distinguishes it from

, and

agomelatine Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other a ...

. The major

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of ramelteon, M-II, is active and has approximately one-tenth and one-fifth the binding affinity of the parent molecule for the human MT₁ and MT₂ receptors, respectively, and is 17- to 25-fold less potent than ramelteon in ''in vitro'' functional assays. Although the potency of M-II at MT₁ and MT₂ receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT_2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes. Ramelteon has no appreciable affinity for the

s or for receptors that bind neuropeptides, cytokines,

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

, noradrenaline,

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

, and opioids. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

Mechanism of action

The activity of ramelteon at the MT₁ and MT₂ receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...

underlying the normal sleep–wake cycle.

Pharmacokinetics

Absorption

The total

absorption Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...

of ramelteon is 84% while its oral bioavailability is 1.8%. The low bioavailability of ramelteon is due to extensive first-pass metabolism. The absorption of ramelteon is rapid, with

peak levels Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharm ...

being reached after approximately 0.75 hours (range 0.5–1.5 hours). Food increases peak concentrations of ramelteon by 22% and overall exposure by 31% and delays the time to peak levels by approximately 0.75 hours. The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of ramelteon are linear across a dose range of 4 to 64 mg. There is substantial

interindividual variability Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, ...

in the peak concentrations and

area-under-the-curve levels In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry). In practice, the dru ...

of ramelteon which is consistent with high first-pass metabolism.

Distribution

The volume of distribution of ramelteon is 73.6 L, which suggests substantial

tissue distribution Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of a drug from one location to another within the body. Once a drug enters into systemic circulation by absorption or direct administration, it mu ...

. The plasma protein binding of ramelteon is 82% independently of concentration. Ramelteon is primarily bound to albumin (70%). The medication is not selectively distributed to red blood cells.

Metabolism

Ramelteon is

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

in the liver primarily by oxidation via

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

and carbonylation. It is also secondarily metabolized to produce glucuronide conjugates. Ramelteon is metabolized mainly by CYP1A2 while

CYP2C Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various com ...

enzymes and

are involved to a minor extent. The

s of ramelteon include M-I, M-II, M-III, and M-IV. Exposure to M-II is approximately 20- to 100-fold higher than to ramelteon.

Elimination

Ramelteon is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

84% in urine and 4% in

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...

. Less than 0.1% of drug is excreted as unchanged ramelteon. Elimination of ramelteon is essentially complete by 96 hours following a single dose. The elimination half-life of ramelteon is 1 to 2.6 hours while the half-life of M-II, the major active metabolite of ramelteon, is 2 to 5 hours. The half-lives of ramelteon and M-II are substantially longer than that of

, which has a half-life in the range of 20 to 45 minutes. Levels of ramelteon and its metabolites at or below the limit of detectability within 24 hours following a dose.

Special populations

Peak levels of ramelteon and overall exposure are about 86% and 97% higher, respectively, in elderly adults compared to younger adults. Conversely, peak levels of M-II are 13% and overall exposure 30% higher in elderly adults than in younger adults. The elimination half-life of ramelteon is 2.6 hours in elderly adults.

History

Ramelteon was first described in the medical literature in 2002. It was approved for use in the United States in July 2005.

Society and culture

Ramelteon has no potential for abuse or

drug dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...

and is not a controlled substance.

Research

Ramelteon, along with other melatonin receptor agonists like

, has been repurposed in clinical trials as an adjunctive treatment for acute manic episodes in subjects with bipolar disorder. Nonetheless, meta-analytic evidence is based on very few trials and does not allow supporting the use of melatonin receptor agonists as adjunctive options for mania in clinical practice, although the small sample size do not allow ruling out their beneficial effect.

References

External links

* {{Portal bar , Medicine Benzofurans Indanes Melatonin receptor agonists Propionamides Sedatives Takeda Pharmaceutical Company brands